Familial risks in urolithiasis in the population of Sweden.

OBJECTIVE: To assess detailed familial risks for medically diagnosed urolithiasis (UL, urinary tract stone disease) based on nationwide hospital and population records. PATIENTS/SUBJECTS AND METHODS: Subjects were identified from the Swedish Multigeneration Register in which there were 211 718 patients with UL. Standardised incidence ratios (SIRs) were calculated by comparison to individuals without a family history of UL. RESULTS: The highest familial SIRs were invariably found for the same (concordant) type of UL: 2.18 for kidney, 2.20 for ureter, and 1.93 for bladder. SIRs increased from 1.84, when one parent was affected, to 3.54 when both parents were affected, which was a multiplicative interaction. The SIR was 1.79 when one sibling was affected but it increased to 24.91 when two siblings were affected. Such excessive risks (5.2% of familial cases) are probably explained by high-penetrant genes. A low SIR of 1.29 between spouses suggested a minor contribution by shared environmental factors on the familial risk. CONCLUSIONS: The results point to underlying genetic causes for the observed familial clustering and establish the genetic landscape of UL. Family histories should be taken in UL diagnostics and prevention could follow guidelines recommended for recurrent UL.

Proteus mirabilis fimbriae- and urease-dependent clusters assemble in an extracellular niche to initiate bladder stone formation.

The catheter-associated uropathogenProteus mirabilisfrequently causes urinary stones, but little has been known about the initial stages of bladder colonization and stone formation. We found thatP. mirabilisrapidly invades the bladder urothelium, but generally fails to establish an intracellular niche. Instead, it forms extracellular clusters in the bladder lumen, which form foci of mineral deposition consistent with development of urinary stones. These clusters elicit a robust neutrophil response, and we present evidence of neutrophil extracellular trap generation during experimental urinary tract infection. We identified two virulence factors required for cluster development: urease, which is required for urolithiasis, and mannose-resistantProteus-like fimbriae. The extracellular cluster formation byP. mirabilisstands in direct contrast to uropathogenicEscherichia coli, which readily formed intracellular bacterial communities but not luminal clusters or urinary stones. We propose that extracellular clusters are a key mechanism ofP. mirabilissurvival and virulence in the bladder.

Evaluation of 21 426 feline bladder urolith submissions to the Canadian Veterinary Urolith Centre (1998-2014).

This study reports emerging trends in feline urolithiasis in Canada during the past 16.8 y, evaluates associations of breed and gender with urolith types, and reports on feline submissions from outside of Canada. Struvite and calcium oxalate uroliths comprised > 90% of all uroliths submitted. In cats, oxalate submissions outnumbered struvite submissions from Canada, Hong Kong, Denmark, and the United Arab Emirates, while Australian struvite submissions outnumbered calcium oxalate submissions. In Canada, the majority of urolith submissions were from domestic cats followed by Himalayan, Persian, and Siamese cats. Males were more likely to form calcium oxalate uroliths and females were more likely to develop struvite uroliths. Compared to domestic short-haired cats, Tonkinese, Burmese, Devon rex, Himalayan, Persian, and Siamese cats were significantly associated with calcium oxalate urolith submission. Egyptian mau, Birman, ocicat, and Siamese breeds were over-represented amongst urate submissions.

Évaluation de 21 426 soumissions d'urolithes de vessie au Centre canadien d'urolithes vétérinaires (1998­2014). Cette étude présente un rapport sur les tendances émergentes pour l'urolithiase féline au Canada pendant les 16,8 dernières années, évalue les associations avec la race et le sexe pour les types d'urolithes et établit un rapport sur les soumissions félines provenant de l'extérieur du Canada. Les urolithes de struvite et d'oxalate de calcium représentaient > 90 % de tous les urolithes soumis. Chez les chats, les soumissions d'oxalate étaient supérieures aux soumissions de struvite pour les échantillons provenant du Canada, de Hong Kong, du Danemark et des Émirats arabes unis, tandis que les soumissions de struvite provenant de l'Australie étaient supérieures aux soumissions d'oxalate de calcium. Au Canada, la majorité des soumissions d'urolithes provenaient de chats domestiques suivis des chats himalayens, persans et siamois. Il était plus probable que les mâles aient des urolithes d'oxalate de calcium et il était plus probable que les femelles développent des urolithes de struvite. Comparativement aux chats domestiques à poil court, les chats tonkinois, burmese, Devon rex, himalayens, persans et siamois présentaient une association importante avec une soumission d'urolithes d'oxalate de calcium. Les races de chat Mau égyptien, birman, ocicat et siamois étaient surreprésentées parmi les soumissions d'urate.(Traduit par Isabelle Vallières).

Association of Cytochrome-17 (MspA1) Gene Polymorphism with Risk of Gall Bladder Stones and Cancer in North India.

BACKGROUND: Cholelithiasis is associated in 54%-98% of patients with carcinoma of the gallbladder, and a high incidence among females suggests a role of female hormones in the etiology of the disease. Cytochrome P450C17α (CYP-17) is a key enzyme involved in estrogen metabolism and polymorphisms in CYP-17 are associated with altered serum levels of estrogens. Thus, we investigated whether the CYP-17 MspA1 gene polymorphism might impact on risk of gall bladder cancers or gallstones, as well as to determine if this gene polymorphism might be linked with estrogen serum levels and lipid profile among the North Indian gall bladder cancer or gallstone patients. MATERIALS AND METHODS: CYP-17 gene polymorphisms (MspA1) were genotyped with PCR-RFLP in cancer patients (n=96), stone patients (n=102), cancer+stone patients (n=52) and age/sex matched control subjects (n=256). Lipid profile was estimated using a commercial kit and serum estrogen was measured using ELISA. RESULTS: The majority of the patients in all groups were females. The lipid profile and estrogen level were significantly higher among the study as compared to control groups. The frequency of mutant allele A2 of CYP17 MspA1 gene polymorphism was higher among cancer (OR=5.13, 95% CI+3.10-8.51, p=0.0001), stone (OR=5.69, 95%CI=3.46-9.37, p=0.0001) and cancer+stone (OR=3.54, 95%CI=1.90-6.60, p=0.0001) when compared with the control group. However there was no significant association between genotypes of CYP17 MspA1 gene polymorphism and circulating serum level of estrogen and lipid profile. CONCLUSIONS: A higher frequency of mutant genotype A1A2 as well as mutant allele A2 of CYP-17 gene polymorphism is significantly associated with risk of gallbladder cancer and stones. Elevated levels of estrogen and an altered lipid profile can be used as predictors ofgall bladder stones and cancer in post menopausal females in India.

Significance of twinkling artifact on ultrasound in the diagnosis of cystine urolithiasis.

Twinkling artifact (TA) refers to the finding characterized by both a high-echoic mass upon B-mode ultrasound (US) and turbulence-like signals over the entire mass without significant blood flow on color Doppler US. TA is a characteristic sign of urolithiasis, and there has been no previous report on this finding in the digestive tract. The authors recently encountered a 2-year 9-month-old boy with cystinuria presenting with an opacified abdominal mass. Although he was originally diagnosed as having calcified stool mass, the finding of TA upon US led to the correct diagnosis of huge urolith (4.2 cm in diameter) in the urinary bladder. Laparotomic stone removal was successfully conducted and the calculus was confirmed to be composed of cystine. The finding of TA upon US facilitates identification of the structure and location of the intra-abdominal mass.

Overexpression of annexin a1 induced by terephthalic acid calculi in rat bladder cancer.

Prolonged cell proliferation in response to irritation by bladder calculi can evoke malignant transformation of the urothelium. However, the molecular mechanisms responsible for calculi-associated bladder carcinogenesis are unknown. We compared the protein expression pattern of rat bladder transitional cell carcinomas (TCCs) induced by terephthalic acid with that of normal bladder tissues using 2-DE. Comparative analysis of the respective spot patterns on 2-DE showed 146 spots that were markedly changed in TCC samples. Subsequently, 56 of the variant protein spots were identified by MALDI-TOF MS. Among them, overexpression of annexin a1 (ANNA1) in rat TCCs was confirmed by Western blotting and real-time RT-PCR analysis. Immunohistochemical staining revealed that ANNA1, usually a cytoplasmic protein in normal urothelium, was translocated to the nucleus in rat bladder cancer cells. In contrast to the animal studies, examination of human clinical specimens showed that ANNA1 expression was reduced in TCC compared to normal urothelium. The expression of ANNA1 was inversely related to the level of differentiation of TCC. Our data suggest that overexpression of ANNA1 is involved in bladder carcinogenesis induced by bladder calculi and that translocation of the protein may be partly responsible for the effect. ANNA1 may serve as a new marker of differentiation for the histopathological grading of human TCC.

Elevated prostaglandin E2 level via cPLA2--COX-2--mPGES-1 pathway involved in bladder carcinogenesis induced by terephthalic acid-calculi in Wistar rats.

To investigate the prostaglandin E2 (PGE2) biosynthetic mechanism in bladder carcinogenesis, we established Wistar rat model of bladder papilloma and transitional cell carcinoma (TCC) induced by 5% terephthalic acid (TPA) treatment. Then, the mRNA level of cytosolic phospholipase A2 (cPLA2), cyclooxygenases (COX)-1 and -2, membrane-bound PGE2 synthases (mPGES)-1 and -2 was detected using reverse transcription polymerase chain reaction (RT-PCR). Immunoblotting was applied to detect the expression of COX-2 protein. Proliferating cell nuclear antigen (PCNA) was determined by immunohistochemistry. In addition, the level of PGE2 was measured by radioimmunoassay (RIA). Bladder papilloma (100%, 8/8) was examined in rats after 24-week treatment, and bladder TCC (80%, 16/20) was found after 48-week treatment. Histopathological changes were not found in control group rats. The incidence of bladder papilloma and TCC in test group was significantly higher than that in control group (P<0.01). The mRNA levels of cPLA2, COX-2 and mPGES-1 in the bladder papilloma and TCC were significantly higher than those in normal bladder (P<0.01), while the mRNA levels of COX-1 and mPGES-2 in TCC were unchanged compared with normal bladder. Bladder TCC exhibited a substantial expression of COX-2 protein. On the contrary, normal bladder tissue barely expresses COX-2 protein. PCNA labeling index (LI) and the level of PGE2 in bladder papilloma are much higher than those in normal bladder (P<0.01), but lower than those in bladder TCC (P<0.05). In conclusion, increasing PGE2 level via cPLA2--COX-2--mPGES-1 pathway may play an important role in rat bladder carcinogenesis. PGE2 may be a biomarker for the development of bladder TCC. cPLA2 and mPGES-1 may be targets for development of novel chemoprevention strategies for bladder TCC.

[Multiple enterolithiasis, coexisting with bladder and gallbladder lithiasis, associated with colon adenocarcinoma]. / Enterolitiasis múltiple, coexistiendo con litiasis biliar y vesical, asociada a adenocarcinoma de colon.

Enteroliths are calculi primarily formed in the intestine. Enterolithiasis is a rare condition frequently associated with intestinal stasis. Usually it causes no symptoms in most cases, but it can be an important diagnostic clue in patients presenting intestinal occlusive symptoms. We report a case of multiple enterolithiasis, very infrequent pathology, coexisting with bladder and gall bladder lithiasis in a patient with colon adenocarcinoma. Diagnosis was made by X-rays and CT images. Calculi were analysed by several methods: chemical, infrared spectroscopy, stereoscopic microscopy and atomic emission spectroscopy; they showed that caluli are made up of organic material and whilokita (calcium and magnesium ortophosphate). No risk factors for lithogenesis were found in this patient excluding the intestinal stasis caused by intestinal narrowing as a result of adenocarcinoma. Genetic factors are suggested as main contributors to hyperlithogenesis observed in this patient. The physiopathological conditions were studied in depth and literature about this subject reviewed.

[Two cases of 2.8-dihydroxyadenine stone with a partial deficiency of adenine phosphoribosyltransferase].

We report two cases of 2.8-dihydroxyadenine stones due to partial deficiency of adenine phosphoribosyltransferase. The first patient is a 41-year-old female. Radiologic examination revealed left radiolucent renal stones and contracted kidney. Left nephrectomy was performed. Infrared spectrometric analysis of the stones revealed 2.8-dihydroxyadenine calculi. The adenine phosphoribosyltransferase activity in lymphocyte (T cell) was 19.5% of the control level. After the operation, the patient was given 300 mg/day of alloprinol. There have been no signs of recurrence. The second patient was a 52-year-old male. Radiologic examination revealed radiolucent stones of the right kidney and the urine bladder. Percutaneous nephrolithotomy and cystolithotripsy were performed. Infrared spectrometric analysis of the stones revealed 2.8-dihydroxyadenine calculi. The adenine phosphoribosyltransferase activity in the lymphocytes (T cell) was 21% of the control level. After the operation the patient was given 200 mg/day of alloprinol and put on a low purine diet. There have been no signs of recurrence.

Incidence of struvite urinary calculi in two ancestral lines of beagles.

In the last 17 years, 55 of 2,125 (2.6%) purebred beagles maintained in a closed colony had urolithiasis. Males comprised 72.7% of the affected animals. All the uroliths except one set in the kidneys were in the urinary bladder, the urethra, or both. All uroliths were nearly pure magnesium ammonium phosphate hexahydrate. Partially inbred beagles had a 10.7% incidence of urolithiasis, compared to a 2.0% incidence in an outbred line.

[Cystinolysinuric lithiasis]. / Litiásis cistinolisinúrica.

Cystinuria is a disease characterized by the excessive elimination of cystine and of dibasic amino acids (lysine, arginine, and ornithine) through urine of homozygotes. This study included 6 children complaining of abdominal pain with or without hematuria. The existence of renal radio-opaque lithiasis was confirmed in 5 of them and in the sixth, it was vesical. The clinical and analytic data were practically normal with the exception of the qualitative test of the amino acid urinary excretion that showed increase in urinary excretion of cystine. Likewise, percentages of tubular reabsorption were pathological in all the patients showing values between 35.4% and 74%. The diagnosis of systini-lysinuric lithiasis was established through amino acid excretion study in the six patients which was below normal; it fluctuated between 36% and 74%. Lysine, together with cystine, was the most frequently affected.

Abnormal ornithine carbamoyltransferase in mice having the sparse-fur mutation.

Mice with the X-chromosomal sparse-fur (spf) mutation frequently have urinary bladder stones composed mostly of orotic acid, which was identified by the following criteria: ultraviolet and infrared absorption, spectra, chromatographic behavior, melting point, and reactivity in a specific color test. This clue led to the discovery that spf-bearing mice have an abnormal form of liver ornithine carbamoyltransferase (carbamoylphosphate:L-ornithine carbamoyltransferase, EC 2.1.3.3). Normal ornithine carbamoyltransferase has maximum activity at pH 7.6-8.0 and 80% of maximum activity at pH 10.0.